Mammals generate immune responses through a complex interplay among various cell types controlled by genes of the major histocompatibility complex (MHC). Thus, in the mouse, genes encoded by the I-region control the interactions of T cells with macrophages and B cells that are required to produce optimal humoral and cellular immune functions. Diverse studies strongly suggest that proteins known as Ia (I-region-associated) antigens present on the surfaces of B cells and macrophages and encoded by genes of the I-region are involved in these cooperative interactions. Although no immune response genes have been mapped in the human MHC (HLA) as yet, the HLA-D region presumably controls man's ability to generate immune responses, based on its similarity to the murine I-region. Alloantisera obtained from individuals immunized with HLA-D incompatible cells detect cell-surface markers designated as D-region-related (DR) antigens and structurally equivalent to murine Ia antigens determined by the IC subregion. Thus, DR antigens may play a crucial role in mediated cell interaction phenomena in humans. To gain insight into how the structure of murine Ia and human DR antigens relates to their function, we propose to: 1) assess the degree of structural homology among allelic forms of DR antigens, 2) determine the degree and nature of structural variation among allelic forms of DR and Ia antigens, and 3) determine whether allelic differences are restricted to one or more regions of these molecules. We propose to use methods that have proven highly successful in analyzing products of the murine MHC.